Fiscal Year 2018 has seen significant progress toward accomplishing both Specific Aims; some of this progress is detailed here. For Aim 1, the first project focuses on the early development of MS lesions. Previously, we studied two critical aspects of lesion development: the small veins around which white matter lesions form, and the short-to-medium-term outcomes of acute lesions. To understand whether the presence of a central vein may help distinguish MS lesions from their mimickers an idea that remains controversial and to which we only partially subscribe we previously developed a rapid imaging approach for clinical 3T MRI called FLAIR*. Two studies to assess the utility of FLAIR* for diagnosis and characterization of MS lesions have been published in the last year (15, 22); we found that FLAIR* is able to significantly improve diagnostic confidence in a variety of settings. The technique is now in use at several centers around the world, and with the North American Imaging in MS (NAIMS) cooperative, we are conducting a multi-center clinical trial to assess whether FLAIR* allows earlier and more confident diagnosis of the disease. With respect to lesion outcomes, we previously established that there are two spatiotemporal patterns in MS lesions: a centrifugal pattern, in which serum contents leak from the center of the lesion and then proceed outward, over the course of minutes to hours, to fill the entire lesion; and a centripetal pattern, in which serum contents first appear on the periphery of the lesion and then proceed inward. These findings have important implications for understanding lesion development and its association with blood-brain-barrier permeability. In further work, we described how these permeability patterns help to determine the fashion in which acute MS lesions evolve into their chronic counterparts. Among other things, we found that very early events, perhaps occurring within the first month after lesion formation, appear to determine the efficacy of tissue repair, possibly including remyelination. In the past year, we have shown that we can reliably identify chronically inflamed lesions on clinical MRI systems (3). This research is ongoing, and based on it we have started a clinical trial to test whether corticosteroids improve lesion repair, in collaboration with our colleagues in the NINDS Neuroimmunology Clinic. We are also planning additional clinical trials over the next several years. We have also increased our focus on the characterization of MS lesions affecting the cerebral cortex, which have proven difficult to detect by MRI (unlike their white matter counterparts). Our approach here has been to evaluate new MRI approaches with potentially higher sensitivity than previously described methods, taking advantage of the 7-tesla research system at NIH and of our collaborations with MRI pulse sequence developers at NIH, in the extramural community, and in industry. In the past year, we have published a study describing a method to more than double the sensitivity for cortical lesion detection (7). We have also followed up our prior discovery of the imaging correlate of inflammation in the leptomeninges (the membranes that surround the brain) (2) by reporting the discovery of a lymphatic vascular system in the dura mater of human and nonhuman primates (1, 13). Additionally under Aim 1, we have continued our work on improving methods for image acquisition and analysis, with MRI (4, 6, 10, 11, 12, 16, 17, 18), PET (5, 8, 9), and CT (20, 23). For Aim 2, we described the imaging and cellular/molecular events in early inflammatory demyelinating lesions that develop in the brains of marmoset monkeys with experimental autoimmune encephalomyelitis (EAE). We previously suggested, using coarse MRI techniques, that the blood-brain barrier becomes locally permeable up to four weeks prior to the onset of demyelination, and we showed that this permeability is associated with a perivascular lymphocytic and mononuclear infiltrate with parenchymal activation of microglia and astrocytes. We have since shown directly that the plasma protein fibrinogen leaks into the brain parenchyma prior to demyelination, and that fibrinogen can also be seen in chronically inflamed lesions in people with MS (14, 19), Ongoing experiments are designed to study the development of lesions in the spinal cord in marmoset EAE, as well as the extent to which those lesions remyelinate. The results will pave the way toward using the marmoset model in preclinical studies to predict the response of people to novel treatments. Finally, we were invited to contribute, and subsequently published, a major review on MS in the New England Journal of Medicine (21).